There are compelling data indicating that cancer and its therapies are associated with cognitive decline (chemo-brain) in certain survivors. Cognitive decline is an important public health issue facing our aging nation since it is a strong predictor f functional decline, hospital admission, mortality, and healthcare costs. For women 60 and older (older), who represent 71% of the three million US breast cancer survivors, cognitive decline is especially salient, since even small declines have negative effects on daily life. While there are multiple studies in younger survivors showing both persistent and late cognitive problems, there are insufficient data on long-term trajectories of and risks for cognitive decline in older survivos since past research has had small samples of older survivors; lacked pre-treatment data; was uncontrolled; and/or did not include follow-up. In recognition of this important evidence gap, the Institute of Medicine issued a recent call for collection of data about factors that influence the course of cancer survivorship in older survivors, stressing cognitive outcomes. In this revised continuation, our multi-disciplinary team will use a bio-behavioral cancer and aging framework to fill this gap by leveraging the Thinking and Living with Cancer (TLC) cohort. TLC is the only prospective cohort of older breast cancer survivors evaluated pre-treatment and 12 months later that includes matched controls. We have made excellent progress, meeting enrollment targets, publishing 19 papers, and presenting two abstracts. We also have provocative preliminary results showing divergent trajectories by treatment and genotype, with APOE ?4 positive chemotherapy-exposed survivors demonstrating dramatically steeper 12-month declines in several cognitive domains than other survivors and controls. Additionally, physical activity tended to decrease and multi-morbidity to increase the odds of 12-month decline. To understand longer-term trajectories of and risks for cognitive decline, we propose to conduct new assessments (24, 36, 48 months) of the TLC cohort, use banked DNA for COMT polymorphism testing, and add objective monitoring of physical activity and measurement of inflammatory markers. The aims are to: 1) ascertain trajectories of longitudinal cognitive function and test for differences in treatment exposure-control groups; 2) identify risk factors for cognitie decline in the 48 months post-enrollment and determine how effects are moderated by treatment exposure (chemotherapy>hormonal>control); and 3) assess how inflammatory products (CRP, IL6, and sTNFRII) co-vary with trajectories of cognition; and test if inflammation mediates effects of physical activity and multi-morbidity on cognitive decline. The results will have high impact by suggesting future mechanistic research and intervention trials, and supporting patient-physician discussions about treatment benefits and harms. Knowledge about whether trajectories of decline plateau, accelerate, or occur as late effects could improve survivorship care planning for older breast cancer survivors.